Asparagine Dependency Is a Targetable Metabolic Vulnerability in TP53-Altered Castration-Resistant Prostate Cancer

Cancer Res. 2024 Sep 16;84(18):3004-3022. doi: 10.1158/0008-5472.CAN-23-2910.

Abstract

TP53 tumor suppressor is frequently altered in lethal, castration-resistant prostate cancer (CRPC). However, to date there are no effective treatments that specifically target TP53 alterations. Using transcriptomic and metabolomic analyses, we have shown here that TP53-altered prostate cancer exhibits an increased dependency on asparagine (Asn) and overexpresses Asn synthetase (ASNS), the enzyme catalyzing the synthesis of Asn. Mechanistically, the loss or mutation of TP53 transcriptionally activated ASNS expression, directly and via mTORC1-mediated ATF4 induction, driving de novo Asn biosynthesis to support CRPC growth. TP53-altered CRPC cells were sensitive to Asn restriction by knockdown of ASNS or L-asparaginase treatment to deplete the intracellular and extracellular sources of Asn, respectively, and cell viability was rescued by Asn addition. Notably, pharmacological inhibition of intracellular Asn biosynthesis using a glutaminase inhibitor and depletion of extracellular Asn with L-asparaginase significantly reduced Asn production and effectively impaired CRPC growth. This study highlights the significance of ASNS-mediated metabolic adaptation as a synthetic vulnerability in CRPC with TP53 alterations, providing a rationale for targeting Asn production to treat these lethal prostate cancers. Significance: TP53-mutated castration-resistant prostate cancer is dependent on asparagine biosynthesis due to upregulation of ASNS and can be therapeutically targeted by approaches that deplete intracellular and extracellular asparagine.

MeSH terms

  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism
  • Animals
  • Asparagine* / metabolism
  • Aspartate-Ammonia Ligase / genetics
  • Aspartate-Ammonia Ligase / metabolism
  • Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor
  • Cell Line, Tumor
  • Cell Proliferation
  • Humans
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice
  • Prostatic Neoplasms, Castration-Resistant* / drug therapy
  • Prostatic Neoplasms, Castration-Resistant* / genetics
  • Prostatic Neoplasms, Castration-Resistant* / metabolism
  • Prostatic Neoplasms, Castration-Resistant* / pathology
  • Tumor Suppressor Protein p53* / genetics
  • Tumor Suppressor Protein p53* / metabolism

Substances

  • Asparagine
  • Tumor Suppressor Protein p53
  • TP53 protein, human
  • ASNS protein, human
  • Aspartate-Ammonia Ligase
  • Activating Transcription Factor 4
  • Mechanistic Target of Rapamycin Complex 1
  • ATF4 protein, human
  • Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor